Antiviral Therapy

Although pegylated interferon (PEG-IFN) and nucleotide/nucleoside analogue (NA) combination therapy is considered to be optimal for accelerating serum hepatitis B surface antigen (HBsAg) reduction, the effect is limited, and the best approach to PEG-IFN treatment for chronic hepatitis B patients during long-term NA therapy has yet to be determined.

A total of 21 hepatitis B e antigen-negative chronic hepatitis B patients whose HBV DNA levels were suppressed to undetectable levels by NA therapy were administrated PEG-IFN-α2a for 48 weeks (sequential therapy: 10, add-on therapy: 11). Factors associated with HBsAg reduction by PEG-IFN therapy were analysed.

During PEG-IFN treatment, HBsAg levels were reduced by 0.48 log IU/ml. More than 1 log IU/ml of HBsAg reduction was observed in eight patients (sequential therapy: six, add-on therapy: two), and one patient with sequential therapy achieved HBsAg loss. By univariate analysis, sequential therapy was marginally associated with more than 1 log IU/ml HBsAg reduction during PEG-IFN treatment (P=0.060). After PEG-IFN treatment, only five patients, including the patient with HBsAg loss, achieved more than 0.5 log IU/ml of HBsAg reduction by 1 year after PEG-IFN treatment. By univariate analysis, sequential therapy was significantly associated with HBsAg reduction after PEG-IFN treatment (P=0.012). In addition, alanine aminotransferase elevation during PEG-IFN therapy and lower serum interleukin-8 level at the end of PEG-IFN treatment were also significantly associated with HBsAg reduction by 1 year after PEG-IFN treatment (P=0.038, P=0.044, respectively).

Sequential therapy may be superior to addon therapy in reducing HBsAg levels during long-term NA therapy in chronic hepatitis B patients.

Haemorrhagic cystitis (HC) is usually a serious complication in allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients. In this study, our aim was to define risk factors and outcomes for patients with HC in an allo-HSCT setting.

We retrospectively evaluated 249 allo-HSCTs performed between 2011 and 2016 in our centre.

HC was diagnosed in 98 patients (39%) at a median of 119 days (range 5–580) and 91 (93%) of the patients had late onset disease. In univariate analysis, HC was related to cytomegalovirus (CMV) reactivation (P<0.001) and BK viraemia (P<0.001); in multivariate analysis, the presence of CMV reactivation was determined to be an independent risk factor (odds ratio: 22.1; 95% CI 1.73, 282.44; P=0.017). There was no association detected between acute graft versus host disease and patients diagnosed with HC within 100 days of transplant. HC was significantly increased by the presence of myelo-ablative conditioning (odds ratio: 31.28; 95% CI 3.98, 246.87; P=0.001) and BK viraemia (odds ratio: 3.93; 95% Cl 1.10, 14.05; P=0.035) in patients with HC grade II and beyond. Forced hydration was recommended in all patients with grade I HC. Patients with HC and clots were treated with continuous bladder irrigation, and 14 of 44 patients with BK viraemia received cidofovir ± ribavirin. Eight of these patients (57%) responded to treatment. Refractory HC was detected in 17 patients (17%) and resolved by a variety of procedures.

This study suggests that CMV reactivation is associated with increased risk of HC in multivariate analysis, however, this result is not confirmed in patients with HC grade II and beyond.

Approximately one-third of patients have durable responses after finite (48-week) treatment with peginterferon alfa-2a. The ability to identify patients likely to respond would be particularly useful in resource-limited settings.

Data from 1,363 peginterferon alfa-2a recipients (955 hepatitis B ‘e’ antigen [HBeAg]-positive and 408 -negative) in six studies were analysed. Baseline scoring systems were developed using generalized additive models and multiple logistic regression analysis to predict virological response (VR; HBV DNA <2,000 IU/ml), alone or combined with alanine aminotransferase (ALT) normalization (CR) at 24 weeks post-treatment.

Based on the final models, points were assigned for age ≥45 (0) or <45 years (1); male (0) or female (1); hepatitis B surface antigen (HBsAg) >25,000 (0), >7,500-≤25,000 (1), >1,250-≤7,500 (2) or ≤1,250 IU/ml (4); HBV DNA >5 (0) or ≤5 log₁₀ IU/ml (2) and ALT ratio >1-7 (0) or either ≤1 or >7 (1). Higher total scores (range 0-9) indicate higher likelihood of response. VR and CR rates were 28.5% (388/1,363) and 24.4% (332/1,363), respectively, and increased with increasing score: score 0-1 (n=257), VR 14.8%, CR 12.8%; score 2-3 (n=711), VR 23.1%, CR 20.1%; score ≥4 (n=395), VR 47.1%, CR 39.5%.

An easy-to-use baseline scoring system for use in settings where HBeAg status and HBV genotypes are unavailable would allow clinicians to identify patients with a low or high chance of achieving a durable post-treatment response to peginterferon alfa-2a. The tool can be used to inform treatment decisions in resource-limited settings.

Cacicol®, a topical eye biopolymer containing a poly-carboxymethylglucose sulfate solution that is a regenerating matrix therapy agent, intended for wound healing of persistent corneal epithelial defects. Based on the chemical composition, we hypothesized that Cacicol® may compete with natural heparan sulfate (HS) which initiates cell surface attachment of herpes simplex virus type-1 (HSV-1), varicella zoster virus (VZV) and human adenovirus (HAdV), three viruses associated with corneal infections.

Cacicol® was compared to vehicle in the following viral strains: HSV-1 SC16 strain and HSV-1 PSLR, a clinical isolate highly resistant to acyclovir and foscarnet; VZV ATH and VZV FLO, two VZV clinical isolates; and HAdV-D37 strain. Viruses in Cacicol® or vehicle were added to cells for 1 h during adsorption then viral replication was assessed by plaque reduction assays on Vero cells for HSV-1 and MeWo cells for VZV and by immunostaining assay on Hep-2 cells for HAdV-D37.

The vehicle had no effect, dose-dependent effects were demonstrated when HSV-1 SC16, HSV-1 PSLR, VZV ATH and VZV FLO were inoculated in the presence of Cacicol®, inhibiting viral replication by 98.4%, 98.9%, 90.1% and 89.0%, respectively. Cacicol® had no antiviral effect against HAdV-D37.

Cacicol® has a significant antiviral activity on HSV-1 and VZV, but not on HAdV-D37. The lack of effect on HAdV is probably because it is less dependent on HS interactions for cell entry. Clinical studies are necessary to determine Cacicol® for an adjunct or alternative therapy of corneal HSV-1 or VZV infection, particularly for the management of antiviral resistant HSV-1.

The remission rates after stopping antivirals in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) vary among studies, while reliable predictors of relapse have not been identified. This prospective study assessed rates and predictors of relapse and retreatment in 57 non-cirrhotic hepatitis B surface antigen (HBsAg)-positive patients with HBeAg-negative CHB who discontinued effective ≥4-year entecavir or tenofovir disoproxil fumarate (TDF) therapy.

A total of 57 patients discontinued therapy after median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir/TDF if they fulfilled predetermined criteria.

During median follow-up of 18 months, no patient died, developed jaundice or liver decompensation. The cumulative relapse rates varied according to HBV DNA and alanine aminotransferase cutoffs; for HBV DNA >2,000 IU/ml, they were 56%, 70% and 72% at 3, 12 and 18 months after stopping entecavir/TDF. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months being significantly affected only by pretreatment fibrosis severity (adjusted relative hazard: 3.43; P=0.015). Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months being higher in patients with lower HBsAg levels at treatment discontinuation.

Our prospective study shows that effective ≥4-year entecavir/TDF therapy can be safely discontinued in non-cirrhotic HBeAg-negative CHB patients. The probability of relapse decreased after month 6. Despite common virological relapses, most patients, particularly those with mild–moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, as a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state.

Epidemiological data suggest that chronic HCV infection (CHC) is associated with increased cardiovascular risk, but it is unknown if it is associated with endothelial dysfunction. We aimed to assess the effect of antiviral treatment on endothelial function in non-cirrhotic adults with CHC.

Self-controlled before and after study. All patients had genotype-1 CHC and were treated with 12 weeks of paritaprevir/ritonavir, ombitasvir and dasabuvir (PrOD), with ribavirin added for those with geno-type-1a infection. Endothelial function was assessed at three time points before antiviral treatment, at treatment weeks 1, 4, 8 and 12, and 12 weeks after the end of treatment. The main assessment tools were reactive hyperaemia peripheral arterial tonometry (RHPAT) and serum concentrations of angiopoietin-2 (Ang-2) and E-selectin.

A total of 16 patients were enrolled. Mean (sd) age was 51.4 (6.9) years and 11 participants (69%) were male. All 16 patients achieved a sustained virological response. The mean (sd) baseline RHPAT index was 2.05 (0.48), and there was no significant change during treatment (mean within-patient change from baseline to end of treatment =-0.23 [0.45]; P= not significant). There was a significant improvement in both mean Ang-2 (baseline 2.44 [0.79] ng/ml, within-patient change -0.60 [0.44]; P<0.001) and E-selectin (baseline 48.7 [21.5] ng/ml, within-patient change -14.4 [13.0]; P<0.001).

Removing HCV viraemia is associated with a significant improvement in endothelial function as measured by serum markers, but not in bedside micro-vascular reactivity. Chronic HCV viraemia may be associated with endothelial cell dysfunction and therefore long-term cardiovascular risk.

Both traditional and HIV-specific risk factors contribute to greater incidence of cardiovascular disease in persons living with HIV (PLWH). Using state-of-the-art, high-resolution magnetic resonance (MR) imaging of the common carotid arteries, this study aimed to evaluate the relationship between carotid vessel wall thickness (c-VWT) and atherosclerotic cardiovascular disease (ASCVD) risk score in PLWH.

Cross-sectional determinations of c-VWT using MR imaging in virally suppressed PLWH without known cardiovascular disease (n=32) and matched controls (n=13) were completed. Clinical data, including ASCVD risk and c-VWT, were compared between groups and regression analyses performed to identify predictors of c-VWT.

PLWH had significantly higher c-VWT (1.15 ±0.11 mm versus 1.08 ±0.08 mm; P=0.02) as well as higher diastolic blood pressure compared to controls, but exhibited no differences in 10-year ASCVD risk score, systolic blood pressure or smoking. Ten-year ASCVD risk score (r=0.53, P-value =0.0002), age (r=0.30, P-value <0.05), triglycerides (r=0.33, P-value =0.03) and waist circumference (r=0.36, P-value =0.02) were significantly associated with increased c-VWT. Among PLWH, c-VWT did not differ by protease inhibitor use. In a multivariate regression analysis, ASCVD risk score was the only variable significantly associated with c-VWT (P-value =0.02), whereas, HIV status was not.

In this cross-sectional study MR imaging demonstrated that c-VWT, a known marker for CVD risk, was increased in PLWH relative to controls, and that 10-year ASCVD risk was closely related to c-VWT, independent of HIV infection. Our data suggest that traditional cardiovascular disease risk factors in PLWH are adequately captured in the ASCVD risk score which was closely associated with subclinical carotid disease.

Ritonavir (RTV) tablets were not available in Thailand until they were manufactured by the Government Pharmaceutical Organization of Thailand. We assessed pharmacokinetics (PK), safety and efficacy of generic RTV-boosted atazanavir (ATV) in virologically suppressed HIV-1-infected Thai adults.

Virologically suppressed HIV-1-infected Thai adults who currently use ATV (either 200 or 300 mg) with Norvir® soft gel capsule (SGC) 100-mg-based regimen were enrolled into this prospective, 48-week single-arm study. Participants switched from Norvir® SGC to generic RTV. Plasma trough concentration (C) was assessed at trough baseline before switching to generic RTV and week 24 in all participants, with the target ATV C of 0.15 mg/l. trough

Plasma HIV-1 RNA and other laboratory safety parameters were assessed until week 48.

Of 100 participants (51% male) enrolled, 50% was using ATV 200 mg and 50% was using 300 mg at the time RTV SGC were changed into generic tablets. All participants used two nucleoside reverse transcriptase inhibitors (NRTIs) as backbone. There were no significant changes in mean (sd) C_trough of RTV (0.20 [0.33] versus 0.23 [0.39]; P=0.21) and ATV (0.83 [0.93] versus 0.88 [0.95]; P=0.62) between baseline and week 24. From entry to week 48, median alanine aminotransferase significantly increased from 25 to 30 IU/l (P=0.001) and total bilirubin significantly decreased from 1.7 to 1.3 (P=0.04). One study drug related grade 3 adverse event was reported. All but one participant maintained plasma HIV-1 RNA <50 copies/ml after 48 weeks.

Generic RTV-boosted ATV showed adequate levels, good tolerability and great efficacy after 48 weeks.